3-184354113-C-T

Position:

chr3-184354113-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_004366.6(CLCN2):c.1709G>A(p.Trp570*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000192 in 1,612,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CLCN2
NM_004366.6 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 4.95

Variant links:

Genes affected

CLCN2 (HGNC:2020): (chloride voltage-gated channel 2) This gene encodes a voltage-gated chloride channel. The encoded protein is a transmembrane protein that maintains chloride ion homeostasis in various cells. Defects in this gene may be a cause of certain epilepsies. Four transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

CLCN2 links:

CLCN2 (HGNC:):

CLCN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 3-184354113-C-T is Pathogenic according to our data. Variant chr3-184354113-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 100629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-184354113-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN2	NM_004366.6 linkuse as main transcript	c.1709G>A	p.Trp570*	stop_gained	15/24	ENST00000265593.9	NP_004357.3	P51788-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN2	ENST00000265593.9 linkuse as main transcript	c.1709G>A	p.Trp570*	stop_gained	15/24	1	NM_004366.6	ENSP00000265593.4		P51788-1

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

150944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.000484

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250326

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135674

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461112

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726874

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000199

AC:

AN:

150944

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73602

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.000484

Alfa

AF:

0.0000260

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 100629). This premature translational stop signal has been observed in individual(s) with epilepsy (PMID: 21703448). This variant is present in population databases (rs201330912, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Trp570*) in the CLCN2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLCN2 are known to be pathogenic (PMID: 23707145). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2018	The W570X variant in the CLCN2 gene has been reported previously as an apparently homozygous pathogenic variant in two unrelated individuals with adult-onset leukodystrophy (Depienne et al., 2013). W570X has also been reported in an individual with idiopathic generalized epilepsy; however, no further information was provided (Klassen et al., 2011). Functional studies show that W570X results in decreased protein expression and abnormal protein localization (Depienne et al., 2013). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W570X variant is observed in 8/276228 (0.003%) alleles in large population cohorts (Lek et al., 2016). We interpret W570X as a pathogenic variant. -

Leukoencephalopathy with mild cerebellar ataxia and white matter edema

Pathogenic:2Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2013	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Epilepsy, idiopathic generalized, susceptibility to, 11

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 29, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -

Familial hyperaldosteronism type II;C2750893:Epilepsy, idiopathic generalized, susceptibility to, 11;C4554120:Leukoencephalopathy with mild cerebellar ataxia and white matter edema

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 05, 2021

- -

CLCN2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 07, 2024

Variant summary: CLCN2 c.1709G>A (p.Trp570X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 250326 control chromosomes. c.1709G>A has been reported in the literature in two unrelated homozygous individuals affected with leukoencephalopathy (Depienne_2013) and in patients with epilepsy (Klassen_2011). This publication also reported experimental evidence and demonstrated decreased mRNA levels in patient derived fibroblasts, consistent with an incomplete nonsense-mediated mRNA decay; in addition, the truncated protein, when expressed in transiently transfected COS7 cells, had an aberrant subcellular localization (Depienne_2013). ClinVar contains an entry for this variant (Variation ID: 100629). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.97

Vest4

0.97

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over